Organ, cell and tissue transplant rejection and the various autoimmune diseases are thought to be primarily the result of a T-cell mediated immune response. This T-cell mediated immune response is initially triggered by helper T-cells which are capable of recognizing specific antigens. These helper T-cells may be memory cells left over from a previous immune response or naive cells which are released by the thymus and may express any of an extremely wide variety of antigen receptors. When one of these helper T-cells recognizes an antigen present on the surface of an antigen presenting cell (APC) or a macrophage in the form of an antigen-MHC complex, the helper T-cell is stimulated to produce IL-2 by signals emanating from the antigen-specific T-cell receptor, co-receptors, and IL-1 secreted by the APC or macrophage. The helper T-cells then proliferate. Proliferation results in a large population of T-cells which are clonally selected to recognize a particular antigen. T-cell activation may also stimulate B-cell activation and nonspecific macrophage responses.
Some of these proliferating cells differentiate into cytotoxic T-cells which destroy cells having the selected antigen. After the antigen is no longer present, the mature clonally selected cells will remain as memory helper and memory cytotoxic T-cells, which will circulate in the body and recognize the antigen should it show up again. If the antigen triggering this response is not a foreign antigen, but a self antigen, the result is autoimmune disease; if the antigen is an antigen from a transplanted organ, the result is graft rejection. Consequently, it is desirable to be able to regulate this T-cell mediated immune response.
CD45 antigen (CD45) is expressed on most leukocytes. Indeed, it was previously thought that a common CD45 antigen was present on all leukocytes, for which reason the receptor was originally known as the Leukocyte Common Antigen (LCA). Monoclonal antibodies (mAbs) to CD45 were proposed as a means of effectively eliminating all leukocytes where desirable, for example, purging an organ to be transplanted of passenger leukocytes prior to transplantation using nonspecific CD45 monoclonal antibody. See, e.g.,WO 91/05568.
It has recently been shown that different isoforms of CD45 are generated by alternate splicing of a single primary transcript of the CD45 gene. These CD45 isoforms include CD45RA, CD45RB, CD45RC, and CD45RO. CD45RA contains the expression product of exon 4 (sometimes referred to as RA) of the CD45 gene; CD45C contains the expression product of exon 6; CD45RB contains the expression product of exon 5; CD45RO does not contain the expression products of any of the three exons 4, 5, or 6. See Hall et al, “Complete Exon-Intron Organization of the Human Leukocyte Common Antigen (CD45) Gene,” J. Immunol., 141, 2781 (1988), herein incorporated by reference and Streuli et al, “Characterization of CD45 and CD45R Monoclonal Antibodies Using Transfected Mouse Cell Lines that Express Individual Human Leukocyte Common Antigens,” J. Immunol., 141, 3910 (1988). The significance of this variable expression, however, has been unclear.
Increased success in clinical organ transplantation has paralleled improvements in techniques for immunosuppression. However, increasingly potent immunosuppressant drugs often produce complications due to their lack of specificity. For example, recipients can become very susceptible to infection. Highly specific immunosuppression is therefore desired.
The ideal specific immunosuppression method would be a treatment which suppresses the action of the lymphocytes responsible for rejection of the particular graft the patient receives without otherwise affecting the immune system.
Therefore, a need exists to durably and selectively suppress or otherwise modulate the immune response in humans, particularly transplant recipients or those afflicted with autoimmune diseases.